We propose two complementary population-based studies to examine the contributions of serologic growth factors and polymorphisms in candidate genes controlling DNA repair, anti-oxidant defense, proliferative processes, and metabolism of hormones and xenobiotic compounds to the initiation of, and progression toward, breast cancer. Both studies will be conducted within an ongoing cohort study of 16,000 women participants of a population-based specimen bank (CLUE II) established in Washing Country Maryland in 1989. The first study will be a nested case-control design of 350 women from the cohort who developed incident breast cancer diagnosed between 1990 and 20003 and 350 matched controls. The second will be a non- concurrent prospective study of 1,700 women from the cohort with biopsy-confirmed benign breast disease (BBD), ascertained via pathology review of records and slides, followed for carcinoma in situ and invasive breast cancer through 2003. BBD will be classified as non-proliferative, proliferative without atypia, or proliferative with atypia according to the criteria of Page and Dupont For women in both studies, genotypes will be assayed using DNA extracted from buffy coat specimens. Serum samples will also be assayed for insulin-like growth factor (IGF-1) and its growth factor binding protein (IGFBP-3). The nested case control study will allow us to detect moderate to strong main effects (OR>2.0) of even low prevalence (i.e. 10%) factors with power of 80% or more. Moderate interaction of effects (gene-gene or gene-environment) having independent strengths of association of at least 2-fold will also be detectable with at least 80% power for factors having prevalences greater than or equal to 10%. We will also explore the development of a novel statistical model of multi-stage progression of BBD toward invasive cancer using data from the BBD cohort. The proposed project will improve our understanding of how molecular factors affect the pre-neoplastic progression to invasive breast carcinoma and consequently improve our ability to identify women most likely to benefit from prevention interventions. It will provide insight into whether molecular risk factors have differential effects on the initiation of, or early-, versus late-pre-neoplastic progression to breast cancer.